Nitric oxide (NO) synthesized in living organisms by the mediation of a nitric oxide synthase (NOS) is considered to be involved in a variety of biological reaction steps.
Forchgott et al. disclose that endothelium-derived relaxing factors (EDRFs) exert strong angiectatic effect and platelet aggregation inhibitory effect (1980). Palmer et al. disclose that the EDRFs essentially are in fact NO (1987). Further studies have revealed that NO is produced in vascular endothelial cells as well as in a variety of tissue cells in the whole body; e.g., the cerebellum, platelets, peripheral nerves, macrophages, polynuclear leucocytes, hepatocytes, Kupffer's cells, kidney mesangial cells, lung parenchyma cells, adrenal vascular smooth muscle, and fibroblasts. In addition to the previously identified effect of relaxing vascular smooth muscle, NO has now been elucidated to function as a neurotransmitter and exert various effects such as a cytotoxic effect on bacteria and oncocytes.
It has also been reported that when NO is overproduced and released in the body, a variety of cells and tissues are damaged because of high reactivity of NO stemming from its chemical instability and NO's effect of relaxing vascular smooth muscle. Particularly, in recent years, the relationship between inflammatory diseases and NO released from activated leucocytes has become of interest. Thus, a drug which inhibits production of NO is envisaged to exert an anti-inflammatory effect.
Meanwhile, interleukin 6 (IL-6) is known to be produced from cells such as monocytes, T cells, B cells, vascular endothelial cells, fibroblasts, and osteoblasts, and to exert a variety of physiological effects including induction effects of differentiating B cells into antibody-producing cells; for synthesizing acute phase protein from hepatocytes; for differentiating cerebral nerve cells; for proliferating and differentiating hematopoietic cells; and for differentiating osteoclasts. In addition, the relationship between IL-6 and inflammation has become of interest.
Chronic rheumatoid arthritis is a type of systemic chronic inflammatory disease in which the joints exhibit anomalous proliferation of connective tissue such as synovial tissue. As has been reported, an excessive amount of IL-6 is present in the serum or synovial fluid of chronic rheumatoid arthritis patients, and proliferation of synovial cells can be suppressed through administration of an antagonist for inhibiting IL-6 activity, such as an IL-6 antibody or an IL-6 receptor.
Among known physiological effects of IL-6, the aforementioned induction effect of differentiating osteoblasts is considered to be a factor responsible for the onset of osteoporosis resulting from bone hyper-resorption of osteoblasts. Accordingly, a drug which inhibits overproduction of IL-6 is envisaged to be effective for chronic inflammatory diseases such as chronic rheumatoid arthritis and for osteoporosis.
Thus, an object of the present invention is to provide a novel compound useful for preventing or treating a disease induced by overproduction of NO or IL-6.